3093 – DHODH INHIBITION SYNERGIZES WITH DNA-DEMETHYLATING AGENTS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES

• Published in: Experimental hematology 2020-08, Vol.88, p.S66-S66
• Main Authors: Kayamori, Kensuke, Kaito, Satoshi, Nagai, Yurie, Koide, Shuhei, Shinoda, Daisuke, Ohshima, Motohiko, Nakajima-Takagi, Yaeko, Yamashita, Masayuki, Zhong, Cheng, Mimura, Naoya, Yamazaki, Satoshi, Miyawaki, Atsushi, Ito, Ryoji, Tohyama, Kaoru, Weetall, Marla, Sakaida, Emiko, Iwama, Atsushi
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2020.09.106

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective and clonal hematopoiesis accompanied by morphological dysplasia and variable cytopenia. Although DNA methyltransferase inhibitors have been used as chemotherapeutic agents for high-risk MDS, the disease become uncontrolled in many cases. Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We herein investigated the efficacy of PTC299, a novel DHODH inhibitor, for MDS. Anti-MDS efficacy of PTC299 was studied using human MDS cell lines and primary MDS cells in vitro. In addition, we assessed the efficacy of PTC299 in xenograft mouse models of MDS by AkaBLI system, which is composed of AkaLumine-HCl and Akaluc. AkaBLI system has improved performance by a factor of 100 to 1,000 over the conventional bioluminescence imaging system composed of D-luciferin and firefly luciferase. Mechanistic studies were conducted via LC-MS/MS, cell cycle analysis, RNA-seq and RT-qPCR. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents to inhibit the growth of MDS cells. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine.